1. Field of the Invention
The invention pertains to a hydrogenation process for preparing piperidine derivatives that minimizes undesirable by-products, increases yield, and simplifies manufacture in eliminating certain purifications otherwise required. In a preferred practice, a specific heterogeneous catalyst is used to hydrogenate an aryl-substituted pyridine, such as 2-phenyl-3-aminopyridine, whereby the pyridine is reduced to piperidine without over-reduction of the phenyl to cyclohexyl.
2. Description of the Prior Art
Piperidine derivatives are used in the synthesis of various compounds, including pharmaceuticals. For example, 2-phenyl-3-aminopyridine is employed as a reactant in the manufacture of antagonists having utility in treating diseases mediated by an excess of substance P. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, members of which exert prompt stimulatory action on smooth muscle tissue. It possesses a characteristic amino acid sequence as described in e.g. U.S. Pat. No. 4,680,283. The involvement of substance P and other tachykinins in the pathophysiology of numerous diseases is known in the art. E.g. substance P has been shown to be involved in the transition of migraine pain, as well as in: central nervous system (CNS) disorders including anxiety and schizophrenia; respiratory and inflammatory diseases such as asthma and rheumatoid arthritis; gastrointestinal disorders such as ulcerative colitis, irritable bowel syndrome and Crohn's disease. Substance P and other tachykinin antagonists have also been reported as useful in treating cardiovascular diseases, allergic conditions, immunoregulation, vascodilation, bronchospasm, reflex or neuronal control of the viscera, senile dementia of the Alzheimer's type, emesis, sunburn and Helicobacter pylori infection.
One particular aryl-substituted pyridine commonly employed in the manufacture of substance P antagonists is 2-phenyl-3-aminopyridine. Manufacture in this regard typically entails the hydrogenation of this compound to form 2-phenyl-3-aminopiperidine. Specifically, hydrogenation (or reduction) of the pyridine ring to piperidine is selectively desired over hydrogenation of the phenyl ring. Industrially, heterogeneous catalysts are preferred for this purpose, with platinum-on-carbon (Pt/C) catalysts being favored. While commercially viable, Pt/C catalysts used in this context heretofore nonetheless manifest certain shortcomings, including importantly the generation of unwanted by-products. For example, these prior catalysts can cause over-reduction of the 2-phenyl-3-aminopyridine starting material to unacceptable levels. Over-reduction in this use setting results in 2-cyclohexyl-3-aminopiperidine, which is caused by the hydrogenation of the phenyl to cyclohexyl. This by-product, when produced at levels known hitherto, in a large scale production facility, necessitates additional purification steps, such as recrystallization, in order that product specifications be met. For example, in a prior art practice approximately 12% to 15% of the 2-phenyl-3-aminopyridine starting material is over-reduced to 2-cyclohexyl-3-aminopiperdine.
The creation of such by-products causes inefficient use of starting material, lowered product yield, and complicates purification, necessitating additional steps to remove of these materials. Accordingly, there is a continuing need to develop a hydrogenation process that evinces less over-reduction, with amelioration of adverse consequences that otherwise attend.